Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids

ABSTRACT

The invention relates to a process for preparing highly functionalized γ-butyrolactams and γ-amino acids by reductive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA analog with desirable medicinal activity.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority from U.S. ProvisionalApplication No. 60/376,991, filed on Jun. 14, 2002.

FIELD OF THE INVENTION

[0002] The invention relates to a process for preparing highlyfunctionalized γ-butyrolactams and γ-amino acids by reductive aminationof mucohalic acid or its derivatives, and discloses a process forpreparing pregabalin, a GABA analog with desirable medicinal activity.

BACKGROUND OF THE INVENTION

[0003] Pregabalin (3-Aminomethyl-5-methyl-hexanoic acid) is a3-substituted γ-amino butyric acid (GABA) analog that exhibits an arrayof useful medicinal properties, as disclosed in WO 93/23383 and U.S.Pat. No. 6,306,910, both of which are assigned to the same assignee asthe instant application.

[0004] Synthetic approaches to pregabalin generally commence from alinear precursor. For instance, WO 93/23383 discloses a route commencingfrom 5-methyl-hexanoic acid that requires 8 transformations. A recentlydisclosed alternative strategy commences with the enantioselectiveconjugate addition of S-αmethylbenzyl amine to 2-Methylene-succinic aciddimethyl ester (Michael J. Mayer, Trip Report, Synthetic Pathways 9^(th)Symposium on the Latest Trends in Organic Synthesis, Albany MolecularSciences Technical Report Vol. 5, No. 19 (2001), p. 9; also available athttp://albmolecular.logical.net/features/tekreps/vol05/no19/last visitedFeb. 6, 2003). The reaction provides a mixture of diastereomers, whichcan be separated, and the requsite diastereomer is then converted topregabalin via 6 additional steps.

[0005] A shortcoming of either of these approaches, particularly inscale-up and production contexts, is that they require a multitude ofsteps and purification operations. As a result, there is a need for aprocess for synthesizing pregabalin and other 3-substituted γ aminoacids that minimizes the total number of synthetic transformations andsimplifies purification steps.

SUMMARY OF THE INVENTION

[0006] These and other needs are met by the present invention whichprovides a process for preparing a compound of formula I

[0007] wherein:

[0008] R₁ is H, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl,heterocyclo, (CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl,wherein n is 0, 1, 2, or 3; and

[0009] R₂ and R_(2′) are each independently H, straight or branched(C₁-C₆)alkyl, a straight or branched (C₂-C₇)alkenyl, (C₃-C₇)cycloalkyl,alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl orsubstituted phenyl;

[0010] comprising:

[0011] (a) treating mucochloric or mucobromic acid 1 wherein X is Cl orBr with R′OH, wherein R′ is (C₁-C₆)alkyl, —CH₂-phenyl, or—CH₂-substituted phenyl, in the presence of acid to provide 2A

[0012] (b) conjugate addition of R₂R_(2′)CM_(0.) wherein R₂ and R_(2′)are as defined above and wherein M₀ is MgBr, CuBr, or B(OH)₂, to 2A, toprovide 3A

[0013] (c) hydrogenation of 3A to provide 4A

[0014] (d) reductive amination of 4A under hydrogenation conditionsusing ammonium formate or R₁NH₂, wherein R₁ is H, (C₁-C₈)alkyl,(C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl, heterocyclo,(CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl, wherein n is0, 1, 2, or 3, followed by hydrolyisis

[0015] What is also provided is a process for preparing pregabalin

[0016] comprising:

[0017] (a) treating mucochloric or mucobromic acid 1 wherein X is Cl orBr with R′OH, wherein R′ is (C₁-C₆)alkyl or —CH₂-aryl, in the presenceof acid, to provide 2

[0018] (b) conjugate addition of

[0019] wherein M₁ is MgBr, CuBr, or

[0020] wherein M₂ is B(OH)₂, to 2 to provide 3B, wherein “———” is absentor is a bond;

[0021] (c) hydrogenation of 3B to provide 4B

[0022] (d) reductive amination of 4B using ammonium formate, followed byhydrolyisis

[0023] What is also provided is a process for preparing a compound offormula I

[0024] wherein:

[0025] R₁ is H, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl,heterocyclo, (CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl,wherein n is 0, 1, 2, or 3; and

[0026] R₂ and R_(2′) are each independently H, straight or branched(C₁-C₆)alkyl, a straight or branched (C₂-C₇)alkenyl, (C₃-C₇)cycloalkyl,alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl orsubstituted phenyl;

[0027] comprising:

[0028] (a) reductive amination of mucochloric or mucobromic acid 1wherein X is Cl or Br, using a reducing agent in the presence ofammonium formate or R₁NH₂, wherein R₁ is (C₁-C₈)alkyl,(C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl, heterocyclo,(CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl, wherein n is0, 1, 2, or 3, and an acid catralyst, to provide 2C

[0029] (b) conjugate addition of R₂R_(2′)CM₀, wherein M₀ is MgBr, CuBr,or B(OH)₂, to 2C to provide 3C

[0030] (c) hydrogenation of 3C to provide 4C

[0031] (d) hydrolysis of 4C

[0032] What is also provided is a process for preparing pregabalin

[0033] comprising:

[0034] (a) reductive amination of mucochloric or mucobromic acid 1wherein X is Cl or Br using a reducing agent in the presence ofbenzylamine or 1-phenyl-ethylamine to provide 2D

[0035] (b) conjugate addition of

[0036] wherein M₁ is MgBr, CuBr, or

[0037] wherein M₂ is B(OH)₂, to 2 to provide 3B, wherein “———” is absentor is a bond;

[0038] (c) hydrogenation of 3D to provide 4D

[0039] ; and

[0040] (d) hydrolysis of 4D

[0041] What is also provided is a process for reductively aminatingmucohalic acid, comprising:

[0042] (a) contacting mucochloric or mucobromic acid 1 wherein X is Clor Br with a reducing agent, an acid catalyst, and R₃NH₂, wherein R₃ isH, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl, heterocyclo,(CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl, wherein n is0, 1, 2, or 3; to provide 2E

DETAILED DESCRIPTION OF THE INVENTION

[0043] The invention processes for preparing 3-substituted γ aminobutyric acids disclosed herein possess a number of advantages. Firstly,they give rise to 3-substituted γ-amino butyric acids in a minimumnumber of steps and under mild conditions. Secondly, they make use ofgenerally inexpensive and readily available reagents. Thirdly, theyexploit the synthetic potential of mucohalic acid.

[0044] Mucochloric acid 1 (2,3-dichloro-4-oxo-2-butenoic acid) andmucobromic acid (2,3-dibromo-4-oxo-2-butenoic acid) are commerciallyavailable and inexpensive starting materials. Both molecules arecharacterized by the presence of a carbon-carbon double bond with Zconfiguration, two halogen atoms, and two carbonyl groups. This highdegree of functionality makes both mucochloric and mucobromic acidparticularly useful building blocks for the synthesis of a variety ofbiologically active heterocycles, such as substituted1,5-dihydropyrrol-2-ones, pyrrolidines, and γ-lactams, and γ-amino acidssuch as pregabalin.

[0045] Mucobromic and mucochloric acid surprisingly have not beencommonly employed in organic synthesis as C-4 building blocks.Presumably, this is because of the many reactive sites in the molecules,their poor stability under basic conditions, and the perception amongthose of ordinary skill in the art of the difficulties associated withthe selective manipulation of the halogen atoms in the presence of theother functional groups.

[0046] In spite of these perceived difficulties, mucohalic acid is thekeystone of the invention processes disclosed herein. As summarized inScheme 1, the processes differ in the relative sequence of the reactionsteps, but both rely on the use of mucohalic acid as a syntheticplatform for the elaboration of the 3-substituted γ amino butyric acidframework. Thus, in Route A, protection of mucohalic acid in Step Aprovides the hemiacetal 2B. In Step B, Conjugate addition of R₂R_(2′)Mto 2B, followed by elimination of halide, provides conjugate additionproduct 3B. Reductive amination of 3B in Step C provides lactam 4B,which may undergoes hydrolysis in situ or in a separate step to provide3-substituted γ amino butyric acid I. In contrast, in Route A′,reductive amination is the first step in the synthetic sequence (StepA′), followed by conjugate addition (Step B′), hydrogenation (Step C′),and hydrolysis (Step D′).

[0047] Pregabalin is readily prepared by either of these routes. Asdepicted in Scheme 2, Route A, mucohalic acid is first converted to theO-benzyl acetal 2B. Organocuprate additon provides the conjugateaddition product 3B. Hydrogenation and dehalogentation gives rise to 4B.Reductive amination under hydrogenation conditions gives rise to lactam5B, which may be hydrolyzed under basic conditions to providepregabalin. Alternatively, as depicted in Route A′ of Scheme 2,reductive amination of mucohalic acid in the first step using benzylamine (shown) or 1-phenylethyl amine provides 2D. Conjugate addition,hydrogenation, and hydrolysis as described for Route A, providespregabalin.

[0048] 1. Definitions

[0049] The following definitions are used, unless otherwise described:halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl,etc. denote both straight and branched groups; but reference to anindividual radical such as “propyl” embraces only the straight chainradical, a branched chain isomer such as “isopropyl” being specificallyreferred to.

[0050] Thus the term “alkyl” means a straight or branched hydrocarbonradical having from 1 to 8 carbon atoms and includes, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, n-heptyl, and the like.

[0051] The term “alkenyl” means a straight or branched hydrocarbonradical having from 2 to 7 carbon atoms and includes, for instance,vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 5-hexenyl, 4-methyl-3-pentenyl, 1-heptenyl, 2 heptenyl, 3heptenyl, 2-methyl-1-hexenyl, 2-methyl-2-hexenyl, 3-methyl-2-hexenyl,3-methyl-3-hexenyl, 3-methyl-1-hexenyl, 4-methyl-1-hexenyl,5-methyl-1-hexenyl;

[0052] The term “cycloalkyl” means a hydrocarbon ring containing from 3to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cycloctyl, decalinyl, norpinanyl, andadamantyl. Where possible, the cycloalkyl group may contain doublebonds, for example, 3-cyclohexen-1-yl. The cycloalkyl ring may beunsubstituted or substituted by one or more substituents selected fromalkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, alkyland dialkylamino, formyl, carboxyl, —CN, —NH—CO—R, —CO—NHR, —CO₂R, —COR,wherein R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,wherein alkyl, aryl, and heteroaryl are as defined herein.

[0053] The term “aryl” means a cyclic or polycyclic aromatic ring havingfrom 5 to 12 carbon atoms, and being unsubstituted or substituted withone or more of the substituent groups recited above for alkyl, alkenyl,and alkynyl groups. Examples of aryl groups include phenyl,2,6-dichlorophenyl, 3-methoxyphenyl, naphthyl, 4-thionaphthyl,tetralinyl, anthracinyl, phenanthrenyl, benzonaphthenyl, fluorenyl,2-acetamidofluoren-9-yl, and 4′-bromobiphenyl.

[0054] The term “alkoxy” means a straight or branched hydrocarbonradical which has from 1 to 8 carbon atoms and is attached to oxygen.Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxy, tert-butoxu, n-pentoxy, n-hexoxy,n-heptoxy, and the like.

[0055] The term “alkylcycloalkyl” means a straight or branchedhydrocarbon radical having from 1 to 8 carbon atoms as defined aboveattached to cycloalkyl group as defined above.

[0056] The term “alkylalkoxy”, means a straight or branched hydrocarbonradical having from 1 to 8 carbon atoms as defined above attached to analkoxy group as defined above.

[0057] The term “alkylphenyl” means a straight or branched hydrocarbonradical having from 1 to 8 carbon atoms as defined above attached to aphenyl or substituted phenyl group.

[0058] The term “alkyphenoxy” means a straight or branched hydrocarbonradical having from 1 to 8 carbon atoms as defined above attached to aphenoxy or substituted group.

[0059] The compounds prepared by the invention process may have one ormore chiral centers and may exist in and be used or isolated inoptically active and racemic forms. It is to be understood that theprocesses of the present invention can give rise to any racemic oroptically-active forms, or mixtures thereof. It is to be furtherunderstood the products of the invention process can be isolated asracemic, enantiomeric, or diastereomeric forms, or mixtures thereof.Purification and characterization procedures for such products are knownto those of ordinary skill in the art, and include recrystallizationtechniques, as well as chiral chromatographic separation procedures aswell as other methods.

[0060] 2. 3-Substituted γ Amino Butyric Acid Synthesis Via5-Alkoxy-3,4-dihalo-5H-furan-2-ones (Route A)

[0061] In Scheme 1, Step A of Route A, mucobromic or mucochloric acid isconverted to the corresponding 5-alkoxy-3,4-dihalo-5H-furan-2-one 2Aupon treatment with a C₁-C₆ alcohol or benzyl or substituted benzylalcohol in the presence of acid. In a typical procedure, a toluenesolution of 1 equivalent of mucohalic acid is combined with 1.5equivalents of benzylacohol and 0.05 equivalent of p-toluene sulfonicacid. The mixture is then heated at reflux for 8 to 24 hours. Theproduct furanone is typically obtained in high yield (85-90 percent).

[0062] In Step B of Route A, conjugate addition of an organocupratereagent R₂R₂CM to 2A, followed by halide elimination, provides thesubstituted furanone 3A. In a typical procedure, the organocuprate isgenerated in situ in the presence of N-methypyrrolidinone (NMP) from acommercially available Grignard reagent (e.g., an alkyl- aryl-, oralkylmagnesium bromide) and copper iodide. If the requisite Grignardreagent is not commercially available, it can be readily preparide fromthe corresponding organohalide compound using one of the many methodsavailable to the skilled artisan. The furanone is then added to theorganocuprate reagent over 5 to 10 minutes at −10 to 0° C., and theresulting mixture is allowed to warm to room temperature.

[0063] In Step C of Route A, hydrogenation of alkylfuranone 3A accordingto a method readily available to the skilled artisan providesdihydrofuranone 4A. In a typical procedure, the furanone is dissolved inTHF, and combined with a tertiary amine base such as triethyl amine, andPd/C. This mixture is hydrogenated in a high pressure reactor untilhydrogen uptake ceases.

[0064] In Step D of Route A, reductive amination of dihydrofuranone 4Awith ammonium formate or R₁NH₂ gives rise to lactam 5A, which may behydrolyzed in situ or isolated and converted to the 3-substituted γamino butyric acid I in a separate step. In a typical procedure,dihydrofuranone 4A is combined in methanol with ammonium formate,triethyl amine, and Pd/C. This mixture is hydrogenated in a highpressure reactor until hydrogen uptake ceases to give rise to a mixtureof the lactoam 5A and the desired ring-opened material I. Submission ofthe mixture to hydrolysis conditions known to the skilled artisan (forexample, treatment with aqueous base), as depicted in Step E, gives riseto I.

[0065] Route A is readily adapted to the synthesis of pregabalin. Step Aremains the same. Step B requires the use of sec-butyl magnesium bromideto generate the necessary organocuprate. Alternatively, the sidechaincan be attached in a Suzuki-type coupling procedure using

[0066] and a palladium catalyst. Steps C, D, and E remain the same.

[0067] 3. 3-Substituted γ Amino Butyric Acid Synthesis Via3,4-Dihalo-1-Substitued-1,5-dihydro-pyrrol-2-ones (Route A′)

[0068] The first step in Route A′ of Scheme 1 for the synthesis of3-substituted γ amino butyric acid requires reductive amination ofmucohalic acid to provide compound 2C.

[0069] A. Route A′/Step A: Reductive Amination of Mucohalic Acid

[0070] As indicated previously, mucobromic and mucochloric acid are notpopular C-4 building blocks because of the many reactive sites in themolecules, their poor stability under basic conditions, and theperception among those of ordinary skill in the art of the difficultiesassociated with the selective manipulation of the halogen atoms in thepresence of the other functionality. As an example, although it is knownthat in the presence of acetic acid, mucobromic or mucochloric acid mayreact with hydrazine or arylhydrazines to form pyridazinones (Scheme 3),the reaction conditions are severe: acetic acid as the solvent, a pH of1 to 2, and temperatures between 60 and 120° C.

[0071] Other than this reported transformation, however, a manifold forthe selective manipulation of the functional groups present in mucohalicacid is unknown.

[0072] i. Reagents

[0073] The reductive amination process described herein accommodates awide variety of reagents and conditions.

[0074] Mucohalic Acid: To begin, either mucobromic or mucochloric acidare suitable for use in the reductive amination process.

[0075] Amine: Also, a wide variety of amines may be used in thereductive amination process, and are represented by the formula R₁NH₂,wherein R₁ is selected from hydrogen or C₁-C₇ alkyl or substituted C₁-C₇alkyl, C₃-C₁₂ cycloalkyl or substituted C₃-C₁₂ cycloalkyl, C₃-C₁₂heterocycloalkyl or substituted C₃-C₁₂ heterocycloalkyl, aryl orsubstituted aryl, or heteroaryl or substituted heteroaryl.

[0076] The primary or secondary alkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl amine used in the invention can be substituted withone or more groups selected from halo, hydroxy, C₁-C₆ alkoxy, carboxy,C₁-C₆ alkoxycarbonyl, aminocarbonyl, halomethyl, dihalomethyl,trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl,pentahaloethyl, thiol, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, andaminosulfonyl, Examples of substituted alkyl groups includefluoromethyl, difluoromethyl, trifluoromethyl, tribromomethyl,hydroxymethyl, 3-methoxypropyl, 3-carboxypentyl,3,5-dibromo-6-aminocarbonyldecyl, and 4-ethylsulfinyloctyl. Examples ofsubstituted alkenyl groups include 2-bromoethenyl,1-amino-2-propen-1-yl, 3-hydroxypent-2-en-1-yl,4-methoxycarbonyl-hex-2-en-1-yl, and2-nitro-3-bromo-4-iodo-oct-5-en-1-yl. Typical substituted alkynyl groupsinclude 2-hydroxyethynyl, 3-dimethylamino-hex-5-yn-1-yl, and2-cyano-hept-3-yn-1-yl.

[0077] The amine used in the reductive amination process may be an aminoacid or its corresponding ester. Typical amino acids include L-lysine,L-alanine, L-arginine L-aspartic acid,N-alpha-benzyloxycarbonyl-L-arginine, L-citrulline, gamma-L-glutamicacid, L-glycine, L-histidine, L-hydroxproline, L-isoleucine, L-leucine,L-lysine, L-methionine, L-ornithine, L-phenylalanine, L-proline,L-pyroglutamic acid, L-serine, L-tryptophan, L-tyrosine, L-valine. Theamine may also be a carboxy terminal-linked peptide having 1 to 10 aminoacids or an addition salt thereof. Such peptides may includeL-arginyl-L-arginine, N-benzyloxycarbonyl-glycyl-L-proline,L-glutaryl-glycyl-arginine, glycyl-glycine, glycyl-L-phenylalanine,glycyl-L-proline, and L-seryl-L-tyrosine, as well as others.

[0078] The amine used in the reductive amination process of the presentinvention may have one or more chiral centers and may exist in and beused or isolated in optically active and racemic forms. It is to beunderstood that the process of the present invention can employ anyracemic, optically-active, polymorphic, geometric, or stereoisomericform, or mixtures thereof, of an amine. It is to be further understoodthe products of the reductive amination process can be isolated asracemic, optically-active, polymorphic, geometric, or stereoisomericforms, or mixtures thereof. Purification and characterization proceduresfor such products are known to those of ordinary skill in the art, andinclude recrystallization techniques, as well as chiral chromatographicseparation procedures as well as other methods.

[0079] However, typically, benzyl amine or S-1-phenyl-ethyl amine isused.

[0080] Reducing Agent: A number of reducing agents can be used in thereductive amination process of the present invention. These reducingagents include sodium triacetoxy borohydride, sodium cyanoborohydride,triethyl silane, Ti(OiPr)₄/NaBH₃CN, borohydride exchange resin,Zn/acetic acid, sodium borohydride/magnesium perchlorate, or zincborohydride/zinc chloride. Preferably, the reducing agent is sodiumtriacetoxyborohydride.

[0081] Acid Catalyst: A variety of acid catalysts can be used in thereductive amination process of the present invention. The acid may be aBronsted, or protic, acid, or a Lewis, or non-protic, acid. Examples ofprotic acids suitable for use in the reductive amination process of thepresent invention include acetic acid, trichloroacetic acid,trifluoroacetic acid, or formic acid. Examples of non-protic acidssuitable for use in the reductive amination process of the instantapplication include magnesium chloride, magnesium triflate, borontrifluoride etherate, AlCl₃, FeCl₃, ZnCl₂, AlBr₃, ZnBr₂, TiCl₄, SiCl₄and SnCl₄.

[0082] ii. Procedure and Stochiometry

[0083] In the reductive amination process of the present invention, themucohalic acid is contacted with the amine, reducing agent, and acidcatalyst. “Contacted” means that the reaction components are typicallymixed in a liquid to form a homogeneous or heterogeneous mixture. Theliquid employed in the reductive amination process of the presentinvention is selected from a polar aprotic solvent. Preferably, thepolar aprotic solvent is selected from tetrahydrofuran, acetonitrile,nitromethane, chloroform, methylene chloride, monochloro ethane, 1,1, or1,2 dichloroethane, 1,1,1 or 1,1,2 tricholoroethane, or 1,1,1,2, or1,1,2,2 tetrachloroethane. More preferred solvents include methylenechloride or chloroform. Mixtures of solvents can also be used.

[0084] The molar equivalents of each of the reaction components (i.e.,mucohalic acid, amine, reducing agent, and acid catalyst) used in thereductive amination process of the instant application are:

[0085] (a) 1 equivalent of mucohalic acid;

[0086] (b) 1 to 5 equivalents of amine;

[0087] (c) 1 to 10 equivalents of reducing agent; and

[0088] (d) sufficient acid catalyst to maintain a pH of about 2 to about7.

[0089] More preferably, the molar equivalents of each of the reactioncomponents (i.e., mucohalic acid, amine, reducing agent, and acidcatalyst) used in the reductive amination process if the instantapplication are:

[0090] (a) 1 equivalent of mucohalic acid;

[0091] (b) 1 to 3 equivalents of amine;

[0092] (c) 1 to 5 equivalents of reducing agent; and

[0093] (d) sufficient acid catalyst to maintain a pH of about 3 to about6.

[0094] Most preferably, the molar equivalents of each of the reactioncomponents (i.e., mucohalic acid, amine, reducing agent, and acidcatalyst) used in the reductive amination process if the instantapplication are:

[0095] (a) 1 equivalent of mucohalic acid;

[0096] (b) 1 to 2 equivalents of amine;

[0097] (c) 1 to 3 equivalents of reducing agent; and

[0098] (d) sufficient acid catalyst to maintain a pH of about 4 to about5.

[0099] In the reductive amination process of the present invention, theinitial concentration of mucohalic acid in the polar aprotic solvent istypically 0.1 to 0.5 M. More preferably, it is 0.15 to 0.45 M. Mostpreferably, it is 0.2 to 0.3 M.

[0100] In the reductive amination process of the present invention, thetemperature is typically from about −25° C. to about 50° C., with lowertemperatures being more suitable for mucobromic acid and highertemperatures being more suitable for mucochloric acid. When mucochloricacid is used, the temperature is more preferably from about about 0° C.to about 40° C., and most preferably from about 10° C. to about 30° C.

[0101] In the reductive amination process of the present invention,reaction times are typically from about 30 minutes to about 5 days; morepreferably, from about 1 hour to 3 days; and most preferably, from about6 hours to 48 hours.

[0102] To demonstrate the present invention process, the reactions ofmucobromic or mucochloric acid with aniline or benzylamine in aceticacid were investigated (Table 4). A mixture of dichloromethane andacetic acid (1:1 v/v) was chosen as the solvent to maintain thestability and solubility of both starting materials. Sodiumtriacetoxyborohydride was used as the reducing agent and the reactionswere conducted at room temperature. Initially γ-lactam 7 was isolated in46% yield, but a solvent screen illustrated that 7 could be obtained in65 to 75% yield once the amount of acetic acid was reduced. TABLE 4Reductive amination in different solvents.^(a)

entry Solvent Yield (%) 1 CH₂Cl₂:HOAc 46 (1:1) 2 1,4-dioxane 48 3 THF 524 CH₃CN 49 5 DCE 68 6 CHCl₃ 66 7 CH₃NO₂ 35 8 CHCl₃ 76 # isolated andpurified by silica gel chromatography and/or crystallization. Productsare estimated to be >95% pure by ¹H NMR and elemental analysis. Allcompounds gave satisfactory elemental analysis data.

[0103] The invention process has been further extended to anilines, withelectron-donating, electron-withdrawing and neutral substituents, aswell as an heteroaromatic amine system (Table 5). Electron-deficientanilines (entries 3, 4 and 9) and electron-rich anilines (entries 2, 5and 7) reacted with almost equal facility and the heteroaromatic amine(entry 6) also underwent selective reaction with reasonable yield. TABLE5 Reductive amination with different “anilines”.^(a)

Entry “Aniline” Product Yield (%) 1

50 2

55 3

65 4

42 5

40 6

55 5

40 6

55 7

60 8

68 9

75 10

20 #silica gel chromatography and/or crystallization. Products areestimated to be >95% pure by ¹H NMR and elemental analysis. Allcompounds gave satisfactory elemental analysis data.

[0104] Mucochloric acid (1) can exist as the open or cyclic form (Scheme6). However, the ultraviolet spectrum in CHCl₃ indicates 1 existspredominantly in the lactone form. Additional spectral data, i.e.vibrational (IR, Raman) and others (NMR and NQR) suggest that thelactone is the dominant form in both the liquid and solid states.Experimental results further support these observations.

[0105] The proposed mechanism for the reductive amination process isdepicted in Scheme 7. Thus, protonation of the aldehyde pushes theequilibrium in favor of the open-form aldehyde. Reductive amination ofthe aldehyde moiety, followed by ring closure and loss of water,provides the cyclic lactam.

[0106] In accordance with this proposed mechanism, reductive aminationwith dialkyl amines and N-alkyl anilines provided substitutedα,β-unsaturated γ-amino acids. All the attempts were successful and allproducts were isolated in acceptable yield. (Table 8). TABLE 8 Reductiveamination with different amines.^(a)

Entry amine product yield (%) 1

67 2

20 3

48 4

89 5^(b)

50/82 6

80 7

85

[0107] Interestingly, attempted reductive aminations with ammoniumformate provided not the expected lactam 8, but instead, lactone 9, in50% yield. When the reaction was repeated without adding ammoniumformate, the yield of 9 increased to 82%. Also, when ammonium acetatewas used, the reaction gave lactone 9 in 80% yield.

[0108] In summary, Step A′ of Scheme 1, Route A′ represents a simple,efficient and selective method to prepareN-benzyl-3,4-dichloro-1,5-dihydropyrrol-2-one, N-aryl (oralkyl)-3,4-dichloro-1,5-dihydropyrrol-2-ones and substituted γ-aminoacids. These products possess a geometrically defined tetrasubstitutedolefin, two differentiated vinyl halides and an acidic sight, and couldbe used in the synthesis of a variety of compounds.

[0109] B. Route A′/Steps B, C, and D

[0110] Steps B, C, and D of Route B are as provided for Steps B, C, andE of Route A.

[0111] The following examples are intended to illustrate variousembodiments of the invention and are not intended to restrict the scopethereof.

EXAMPLES

[0112] Route A, Scheme 2

[0113] Step A: 5-Benzyloxy-3,4-dihalo-5H-furan-2-one.

[0114] Mucohalic acid (0.4-0.6 mol, 1 equivalent), benzyl alcohol (1.5equivalents), and para-toluenesulfonic acid (0.05 equivalent) werecombined in 1000 mL toluene and in an apparatus equipped with a DeanStark Strap. The mixture was heated at reflux until water collection inthe Dean Stark Trap had ceased. The mixture was then cooled to roomtemperature. The toluene was removed in vacuo at 35-40° C. to leave thecrude product as a very pale amber oil. The crude material was purifiedby column chromatography on silica gel eluting with 55, then 10% ethylacetate in heptane.

[0115] 1. 5-Benzyloxy-3,4-dichloro-5H-furan-2-one. Prepared as providedin Procedure A. 95% yield. ¹H NMR (CDCl₃, 300 MHz) δ7.3 (s, 5H), 5.92(s, 1H), 4.95 (d, 1H), 4.89 (d, 1H). Elemental Analysis Observed(Theroretical) for C₁₀H₈Cl₂O₃: C, 51.12(50.99); H, 2.92(3.11); N,<0.05(0.00); Cl, 27.19 (27.37).

[0116] 2. 5-Benzyloxy-3,4-dibromo-5H-furan-2-one. Prepared as providedin Procedure A. 100% yield. ¹H NMR (CDCl₃, 300 MHz) δ7.3 (s, 5H), 5.92(s, 1H), 4.95 (d, 1H), 4.89 (d, 1H). Elemental AnalysisObserved(Theroretical) for C₁₀H₈Br₂O₃: C, 38.62(37.97); H, 2.30(2.32);N, <0.05(0.00); Br, 44.71 (45.92).

[0117] Step B: 5-Benzyloxy-3-halo-4-isopropyl-5H-furan-2-one.

[0118] Alternative 1: Via Cuprate Addition

[0119] 5-Benzyloxy-3,4-dihalo-5H-furan-2-one (0.03-0.15 mol, 1equivalent), 1-methyl-2-2pyrrolidinone (NMP) (excess), and copper iodide(1 equivalent) were combined and stirred at room temperature under aninert atmosphere. After about 30 minutes, the resulting tan suspensionwas cooled to about −15 to about −20° C., and isobutylmagnesium bromide(1.5 equivalents) was added dropwise as a 2.0 M solution in diethylether. The reaction mixture was then quenched with a saturated solutionof aqueous ammonium chloride, and extracted with methyl tertbutyl etherto provide the crude product as an amber oil. Purification by columnchromatography on silica gel eluting with 10% ethyl acetate in heptaneprovided the product as a colorless oil.

[0120] 1. 5-Benzyloxy-3-chloro-4-isopropyl-5H-furan-2-one. 70% yield. MS(AP+) 281.0.

[0121] 2. 5-Benzyloxy-3-bromo-4-isopropyl-5H-furan-2-one. 70% yield. MS(AP+) 325.0.

[0122] Alternative 2: Via Suzuki Coupling

[0123] 5-Benzyloxy-3,4-dihalo-5H-furan-2-one (1 equivalent), boronicacid (2 equivalents, cesium fluoride (2.5 equivalents, PdCl₂(PPh₃)₂(0.05 equivalent), and triethylbenzyl ammonium chloride (0.05equivalent) were combined. To this mixture was added a nitrogen-purgedtoluene and water solvent mixture. The reaction mixture was stirred atroom temperature over night and then quenched with 2N aqueous HCl andextracted with 100 mL toluene. The extract was concentrated in vacuo toprovide the crude product as a pale orange oil which was purified bycolumn chromatography on silica gel eluting with 10% ethyl acetate inheptane.

[0124] 2. 5-Benzyloxy-3-bromo-4-isopropyl-5H-furan-2-one. 30% yield. MS(AP+) 325.0.

[0125] Step C: 5-Benzyloxy-4-isopropyl-dihydro-furan-2-one

[0126] A mixture of 5-Benzyloxy-3-halo-4-isopropyl-5H-furan-2-one (5mmol, 1 equivalent) and triethyl amine (1.2 equivalents) was dissolvedin 65 mL THF. The mixture was transferred to a high pressure reactor.Pd/C (0.3 g) was added, and the mixture was hydrogenated with stirringunder 40 pounds per square inch (psi) of hydrogen. The mixture washydrogenated until hydrogen uptake ceased (about 3 hours). The Pd/Ccatalyst was filtered out and the solvent was removed in vacuo. Theresidue was diluted with ethyl acetate, washed with saturated aqueousammonium chloride and dried over magnesium sulfate. The extract wasconcentrated in vacuo to give the product as a colorless oil.

[0127] 1. From 5-Benzyloxy-3-chloro-4-isopropyl-5H-furan-2-one. 38%yield. MS (AP+) 249.1.

[0128] 2. From 5-Benzyloxy-3-bromo-4-isopropyl-5H-furan-2-one. 83%yield. MS (AP+) 249.1

[0129] Steps D/E: 3-Aminomethyl-4-methyl-pentanoic Acid (Pregabalin)

[0130] 5-Benzyloxy-4-isopropyl-dihydro-furan-2-one was hydrogenated in ahigh pressure reactor as provided above in Step C. Thus, 1.3 g of5-benzyloxy-4-isopropyl-dihydro-furan-2-one was combined with 1.7 g ofammonium formate, 0.3 g of 20% Pd/C, 1.7 g of ammonium formate and 0.07g of [Ir(COD)Cl]₂ in 25 mL of methanol. The mixture was hydrogentated at70° C. and 20 pounds per square inch of pressure until hydrogen uptakeceased (about 7 hours) to provide a mixture of pregabalin (M+160.1)contaminated with 4-isopropyl-pyrrolidin-2-one (M+142.1).

[0131] The mixture may be submitted to base hydrolysis to provideexclusively pregabalin.

[0132] Route A′, Scheme 1

[0133] Step A′. Reductive Amination of Mucohalic Acid with Benzylamine.

[0134] Sodium triacetoxyborohydride (6.4 g, 3.0 equivalents) was addedslowly to a mixture of mucohalic acid (1 equivalent) and benzyl amine(1.1 equivalent) in chloroform (50 mL). The reaction mixture was stirredat approximately 25° C. for 24 hours. The reaction mixture was themquenched with water (200 mL) and washed with water (100 mL). The organiclayer was dried over magnesium sulfate and concentrated in vacuo to give1.28 g of the product which was further purified by silica gel columnchromatograpy to provide the lactam (1.59 g, 66% yield. ).

[0135] Reductive Amination of Mucochloric Acid with(R)-1-phenylethylamine.

[0136] Following the procedure as provided above, provided an 89% yieldof the product lactam after purification.

[0137] All patents, and patent documents are incorporated by referenceherein, as though individually incorporated by reference. The inventionhas been described with reference to various specific and preferredembodiments and techniques. However, it should be understood that manyvariations and modifications may be made while remaining within thespirit and scope of the invention.

What is claimed is:
 1. A process for preparing a compound of formula I

wherein: R₁ is H, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl,heterocyclo, (CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl,wherein n is 0, 1, 2, or 3; and R₂ and R_(2′) are each independently H,straight or branched (C₁-C₆)alkyl, a straight or branched(C₂-C₇)alkenyl, (C₃-C₇)cycloalkyl, alkylcycloalkyl, alkylalkoxy,alkylphenyl, alkyphenoxy, phenyl or substituted phenyl; comprising: (a)treating mucochloric or mucobromic acid 1 wherein X is Cl or Br withR′OH, wherein R′ is (C₁-C₆)alkyl, —CH₂-phenyl, or —CH₂-substitutedphenyl in the presence of acid to provide 2A

(b) conjugate addition of R₂R_(2′)CM₀ wherein R₂ and R_(2′) are asdefined above and wherein M₀ is MgBr, CuBr, or B(OH)₂, to 2A, to provide3A

(c) hydrogenation of 3A to provide 4A

(d) reductive amination of 4A under hydrogenation conditions usingammonium formate or R₁NH₂, wherein R₁ is H, (C₁-C₈)alkyl,(C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl, heterocyclo,(CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl, wherein n is0, 1, 2, or 3, followed by hydrolyisis


2. The process of claim 1, step (a) wherein R′OH is benzyl alcohol. 3.The process of claim 1, step (b), wherein R₂R₂CM₀ is


4. The process of claim 1, step (c) using Pd/C as a catalyst in thepresence of triethyl amine.
 5. The process of claim 1, step (d) whereinthe reductive amination is effected under hydrogenation conditions usingammonium formate, triethyl amine, and Pd/C.
 6. A process for preparingpregabalin

comprising: (a) treating mucochloric or mucobromic acid 1 wherein X isCl or Br with benzyl amine in the presence of acid, to provide 2

(b) conjugate addition of

wherein M₁ is MgBr, CuBr, or

wherein M₂ is B(OH)₂, to 2 to provide 3B, wherein “———” is absent or isa bond;

(c) hydrogenation of 3B to provide 4B

(d) reductive amination of 4B using ammonium formate, followed byhydrolyisis


7. A process for preparing a compound of formula I

wherein: R₁ is H, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl,heterocyclo, (CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl,wherein n is 0, 1, 2, or 3; and R₂ and R_(2′) are each independently H,straight or branched (C₁-C₆)alkyl, a straight or branched(C₂-C₇)alkenyl, (C₃-C₇)cycloalkyl, alkylcycloalkyl, alkylalkoxy,alkylphenyl, alkyphenoxy, phenyl or substituted phenyl; comprising: (a)reductive amination of mucochloric or mucobromic acid 1 wherein X is Clor Br, using a reducing agent in the presence of ammonium formate orR₁NH₂, wherein R₁ is (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl,(CH₂)_(n)-aryl, heterocyclo, (CH₂)_(n)-heterocyclo, heteroaryl, or(CH₂)_(n)-heteroaryl, wherein n is 0, 1, 2, or 3, and an acid catralyst,to provide 2C

(b) conjugate addition of R₂R_(2′)M₀ wherein M₀ is MgBr, CuBr, orB(OH)₂, to 2C to provide 3C

(c) hydrogenation of 3C to provide 4C

(d) hydrolysis of 4C


8. The process of step (a) of claim 7, wherein the R₁NH₂ is benzylamineor 1-phenylethyl amine.
 9. The process of step (a) of claim 7, whereinthe reducing agent is selected from sodium triacetoxy borohydride,sodium cyanoborohydride, triethyl silane, Ti(OiPr)₄/NaBH₃CN, borohydrideexchange resin, Zn/acetic acid, sodioum borohydride/magnesiumperchlorate, or zinc borohydride/zinc chloride.
 10. The process of step(a) of claim 7, wherein the reducing agent is sodium triacetoxyborohydride.
 11. The process of step (a) of claim 7, wherein the acidcatalyst is selected from acetic acid, trichloroacetic acid,trifluoroacetic acid, formic acid, magnesium chloride, magnesiumtriflate, boron trifluoride etherate, AlCl₃, FeCl₃, ZnCl₂, AlBr₃, ZnBr₂,TiCl₄, SiCl₄ and SnCl₄.
 12. The process of step (a) of claim 7, whereinthe acid catalyst is acetic acid.
 13. The process of step (a) of claim7, wherein the stochiometry of the reaction components is: (a) 1equivalents of mucochloric acid; (b) 1 to 5 equivalents of amine; (c) 1to 10 equivalents of reducing agent; and (d) HOAc sufficient to maintaina pH of about 2 to about
 7. 14. The process of step (a) of claim 7,wherein the stochiometry of the reaction components is: (a) 1equivalents of mucochloric acid; (b) 1 to 3 equivalents of amine; (c) 1to 5 equivalents of reducing agent; and (d) HOAc sufficient to maintaina pH of about 3 to about
 6. 15. The process of step (a) of claim 7,wherein the stochiometry of the reaction components is: (a) 1equivalents of mucochloric acid; (b) 1 to 2 equivalents of amine; (c) 1to 3 equivalents of reducing agent; and (d) HOAc sufficient to maintaina pH of about 4 to about
 5. 16. The process of step (a) of claim 7,wherein contacting comprises mixing in a liquid at a sufficientconcentration and at sufficient temperatures and for sufficient times toallow formation of the resulting product.
 17. The process of step (a) ofclaim 7, wherein the liquid is a polar non protic solvent andcombinations or mixtures thereof.
 18. The process of step (a) of claim7, wherein the solvent is selected from tetrahydrofuran, acetonitrile,nitromethane, chloroform, methylene chloride, monochloro ethane, 1,1, or1,2 dichloroethane, 1,1,1 or 1,1,2 tricholoroethane, or 1,1,1,2, or1,1,2,2 tetrachloroethane, or combinations or mixtures thereof.
 19. Theprocess of step (a) of claim 7, wherein the temperature is from about−25° C. to about 50° C.
 20. The process of step (a) of claim 7, whereinthe temperature is from about 0° C. to about 40° C.
 21. The process ofstep (a) of claim 7, wherein the temeperature is form about 10° C. toabout 30° C.
 22. The process of step (a) of claim 7, wherein thetemperature is from about 12.5° C. to about 27.5° C.
 23. The process ofstep (a) of claim 7, wherein the time is from about 30 minutes to about5 days.
 24. The process of step (a) of claim 7, wherein the time is fromabout 1 hour to about 3 days.
 25. The process of step (a) of claim 7,wherein the time is from about 6 hours to 48 hours.
 26. The process ofstep (a) of claim 7, wherein the time is from about 12 hours to 36hours.
 27. The process of step (b) of claim 7 as provided in claim 3.28. The process of step (c) of claim 7 as provided in claim
 4. 29. Aprocess for preparing pregabalin

comprising: (a) reductive amination of mucochloric or mucobromic acid 1wherein X is Cl or Br using sodium triacetoxy borohydride in thepresence of benzylamine or 1-phenyl-ethylamine to provide 2D

(b) conjugate addition of

to provide 3B, wherein “———” is absent or is a bond;

(c) hydrogenation of 3D to provide 4D

(d) base hydrolysis of 4D


30. A process for reductively aminating mucohalic acid, comprising: (a)contacting mucochloric or mucobromic acid 1 wherein X is Cl or Br withsodium triacetoxyborohydride, acetic acid, and R₃NH₂, wherein R₃ is H,(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, (CH₂)_(n)-aryl, heterocyclo,(CH₂)_(n)-heterocyclo, heteroaryl, or (CH₂)_(n)-heteroaryl, wherein n is0, 1, 2, or 3; to provide 2E